Dataset Information

De novo design of potent and selective mimics of IL-2 and IL-15.

ABSTRACT: We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor ??c heterodimer (IL-2R??c) but have no binding site for IL-2R? (also called CD25) or IL-15R? (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2R??c with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2R? and IL-15R?. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2R??c, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

SUBMITTER: Silva DA

PROVIDER: S-EPMC6521699 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

De novo design of potent and selective mimics of IL-2 and IL-15.

Silva Daniel-Adriano DA Yu Shawn S Ulge Umut Y UY Spangler Jamie B JB Jude Kevin M KM Labão-Almeida Carlos C Ali Lestat R LR Quijano-Rubio Alfredo A Ruterbusch Mikel M Leung Isabel I Biary Tamara T Crowley Stephanie J SJ Marcos Enrique E Walkey Carl D CD Weitzner Brian D BD Pardo-Avila Fátima F Castellanos Javier J Carter Lauren L Stewart Lance L Riddell Stanley R SR Pepper Marion M Bernardes Gonçalo J L GJL Dougan Michael M Garcia K Christopher KC Baker David D

Nature 20190109 7738

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγ<sub>c</sub> heterodimer (IL-2Rβγ<sub>c</sub>) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse ...[more]

PMID: 30626941

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Project description:We have previously reported the development and evaluation of a computational program to assist in the design of hydrophobic cores of proteins. In an effort to investigate the role of core packing in protein structure, we have used this program, referred to as Repacking of Cores (ROC), to design several variants of the protein ubiquitin. Nine ubiquitin variants containing from three to eight hydrophobic core mutations were constructed, purified, and characterized in terms of their stability and their ability to adopt a uniquely folded native-like conformation. In general, designed ubiquitin variants are more stable than control variants in which the hydrophobic core was chosen randomly. However, in contrast to previous results with 434 cro, all designs are destabilized relative to the wild-type (WT) protein. This raises the possibility that beta-sheet structures have more stringent packing requirements than alpha-helical proteins. A more striking observation is that all variants, including random controls, adopt fairly well-defined conformations, regardless of their stability. This result supports conclusions from the cro studies that non-core residues contribute significantly to the conformational uniqueness of these proteins while core packing largely affects protein stability and has less impact on the nature or uniqueness of the fold. Concurrent with the above work, we used stability data on the nine ubiquitin variants to evaluate and improve the predictive ability of our core packing algorithm. Additional versions of the program were generated that differ in potential function parameters and sampling of side chain conformers. Reasonable correlations between experimental and predicted stabilities suggest the program will be useful in future studies to design variants with stabilities closer to that of the native protein. Taken together, the present study provides further clarification of the role of specific packing interactions in protein structure and stability, and demonstrates the benefit of using systematic computational methods to predict core packing arrangements for the design of proteins.

Dataset Information

De novo design of potent and selective mimics of IL-2 and IL-15.

Publications

De novo design of potent and selective mimics of IL-2 and IL-15.

Similar Datasets

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